Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids
- Bioorg Med Chem Lett. 2017 Feb 15;27(4):755-758. doi: 10.1016/j.bmcl.2017.01.043.
- 1. Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
- 2. KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA.
- 3. Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Fiske Drug Discovery Laboratory, University of Virginia, Charlottesville, VA 22908, USA.
- 4. KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA. Electronic address: [email protected].
A sulfonamidebenzamide series was assessed for anti-kinetoplastid Parasite activity based on structural similarity to the antiparasitic drug, nifurtimox. Through structure-activity optimization, derivatives with limited mammalian cell toxicity and increased potency toward African trypanosomes and Leishmania promastigotes were developed. Compound 22 had the best potency against the trypanosome (EC50=0.010μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC50>25μM). While the chemotype originated from an unrelated optimization program aimed at selectively activating an apoptotic pathway in mammalian Cancer cells, our preliminary results suggest that a distinct mechanism of action from that observed in mammalian cells is responsible for the promising activity observed in parasites.